title: The lantibiotic mersacidin is a strong inducer of the cell wall stress response of Staphylococcus aureus.
abstract: BACKGROUND
  The lantibiotic mersacidin is an antimicrobial peptide of 20 amino acids that is ribosomally produced by Bacillus sp. strain HIL Y-85,54728. Mersacidin acts by complexing the sugar phosphate head group of the peptidoglycan precursor lipid II, thereby inhibiting the transglycosylation reaction of peptidoglycan biosynthesis.
  
  
  RESULTS
  Here, we studied the growth of Staphylococcus aureus in the presence of subinhibitory concentrations of mersacidin. Transcriptional data revealed an extensive induction of the cell wall stress response, which is partly controlled by the two-component regulatory system VraSR. In contrast to other cell wall-active antibiotics such as vancomycin, very low concentrations of mersacidin (0.15xMIC) were sufficient for induction. Interestingly, the cell wall stress response was equally induced in vancomycin intermediately resistant S. aureus (VISA) and in a highly susceptible strain. Since the transcription of the VraDE ABC transporter genes was induced up to 1700-fold in our experiments, we analyzed the role of VraDE in the response to mersacidin. However, the deletion of the vraE gene did not result in an increased susceptibility to mersacidin compared to the wild type strain. Moreover, the efficacy of mersacidin was not affected by an increased cell wall thickness, which is part of the VISA-type resistance mechanism and functions by trapping the vancomycin molecules in the cell wall before they reach lipid II. Therefore, the relatively higher concentration of mersacidin at the membrane might explain why mersacidin is such a strong inducer of VraSR compared to vancomycin.
  
  
  CONCLUSIONS
  In conclusion, mersacidin appears to be a strong inducer of the cell wall stress response of S. aureus at very low concentrations, which reflects its general mode of action as a cell wall-active peptide as well as its use of a unique target site on lipid II. Additionally, mersacidin does not seem to be a substrate for the resistance transporter VraDE.
authors.affiliation: Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University of Bonn, Sigmund-Freud-Str, 25, 53105 Bonn, Germany. peter.sass@mibi03.meb.uni-bonn.de
authors.forename: Peter
authors.initials: P
authors.lastname: Sass
authors.forename: Andrea
authors.initials: A
authors.lastname: Jansen
authors.forename: Christiane
authors.initials: C
authors.lastname: Szekat
authors.forename: Vera
authors.initials: V
authors.lastname: Sass
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Sahl
authors.forename: Gabriele
authors.initials: G
authors.lastname: Bierbaum
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics; D001430:Bacteriocins / Q000494:pharmacology*; D002473:Cell Wall / Q000187:drug effects*; D017353:Gene Deletion; D020869:Gene Expression Profiling; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development
chemical_list: D018528:ATP-Binding Cassette Transporters; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001430:Bacteriocins; D010455:Peptides; C069959:mersacidin